tbuckley/cabot-search huggingface dataset:
Abstract PO019: Gas6/Axl signaling induces PRAME expression in hepatocellular carcinoma
Authors: Viola Hedrich, Doris Chen, Heidemarie Huber, Wolfgang Mikulits
Journal: Clinical Cancer Research (2022)

Abstract The receptor tyrosine kinase Axl, binding to its ligand Gas6, fosters oncogenic effects during the progression of hepatocellular carcinoma (HCC) which is accompanied by increased mortality of patients. The specific role of Gas6/Axl signaling in neoplastic hepatocytes and its pathophysiological consequences are poorly understood at the current stage of research. We aimed at identifying and functionally analyzing targets of Gas6/Axl signaling in HCC by exploiting well-characterized human HCC tumor models. HCC cells transformed by epithelial to mesenchymal transition (EMT) and expressing high levels of Axl or harboring CRISPR/Cas9-mediated Axl deficiency, the latter in absence or presence of Axl reconstitution, were subjected to Gas6 stimulation and subsequent RNA-seq analysis. Bioinformatics and VENN relations were applied to identify novel targets of the Gas6/Axl axis. Expression of Gas6/Axl targets was assessed in publicly available HCC patient datasets and in HCC tissue microarrays. In vitro analysis was performed including gain and loss of functions studies to unravel target genes contribution to EMT and HCC progression. RNA-seq analyses revealed PRAME (preferentially expressed antigen in melanoma) and C15orf48 among others as novel targets of Gas6/Axl. Notably, these target genes showed elevated expression levels in Axl-stratified HCC patients and significant impact on patient survival. Pharmacological or genetic interference with Axl signaling resulted in strongly reduced expression of PRAME and C15orf48, suggesting bona fide targets of Gas6/Axl signaling. PRAME expression positively regulated 2D cell migration and invasion of 3D hepatospheres while proliferation and survival of HCC cells remained unaffected by altered PRAME levels. In accordance, PRAME expression strongly associated with a mesenchymal-like phenotype in human HCC. Intriguingly, HCC patients expressing PRAME correlated with Axl expression and vascular invasion in a large proportion of HCC patients. Our study demonstrates that PRAME is a novel target of Gas6/Axl signaling in HCC linked to EMT. Translation of in vitro findings into the HCC patient situation provides first insights that PRAME plays a crucial role in HCC progression. Citation Format: Viola Hedrich, Doris Chen, Heidemarie Huber, Wolfgang Mikulits. Gas6/Axl signaling induces PRAME expression in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO019.
Abstract IA02: The good and the bad sides of tertiary lymphoid structures in liver cancer
Authors: Eli Pikarsky
Journal: Clinical Cancer Research (2022)

Abstract Tertiary lymphoid structures (TLSs) are formed in chronically inflamed tissues in response to stress. They form an in situ source for adaptive immune responses, and are considered the frontal command posts of the adaptive immune system. In cancer, they were first recognized to be associated with a good prognosis (e.g. in colorectal cancer and melanoma). Later on, we and others noted that in some cancers their presence can be associated with worse prognosis. In particular, we showed that they can form microniches in which tumor cells can proliferate, depending on cues that are derived from TLS residing cells. Recently, several studies showed that TLSs are important in responding to immune checkpoint inhibitors, indicating that T cell exhaustion could play a role in TLS dysfunction. We hypothesized, that similar to single cells, TLSs can also become dysfunctional, explaining why in particular cases they can be associated with a bad outcome in cancer. Using a mouse model of TLS dependent liver cancer we find that T cell exhaustion is prevalent in pro-tumorigenic TLSs in the liver, and dissect the cell types that are responsible for this immunopathologic state. Our studies of human tissues are in line with the notion that TLS dysfunction correlates with T cell exhaustion in TLSs. Citation Format: Eli Pikarsky. The good and the bad sides of tertiary lymphoid structures in liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA02.
Abstract IA05: Immune mechanisms driving carcinogenesis in NASH
Authors: Mathias Heikenwälder
Journal: Clinical Cancer Research (2022)

Abstract In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multifactorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to the single-cell level. Still, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune checkpoint inhibitors do not work as efficiently. Whereas much effort has been invested in elucidating the role of innate immune response in the hepatic NAFLD microenvironment, only in the past decade have novel critical roles been unraveled for T cells in driving chronic inflammation toward HCC. The metabolic and immune microenvironment interact to recreate a tumor-promoting and immune-suppressive terrain, responsible for resistance to anticancer therapy. Here, I will illustrate the cellular crosstalk with other immune cells, regulatory networks or stimulatory effects of these interactions, and role of the metabolic microenvironment in influencing immune cell functionality in the context of NAFLD and HCC. Citation Format: Mathias Heikenwälder. Immune mechanisms driving carcinogenesis in NASH [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA05.
Abstract IA21: Molecular Pathogenesis and Cells of Origin of Intrahepatic Cholangiocarcinoma
Authors: Sumera I Ilyas
Journal: Clinical Cancer Research (2022)

Abstract Intrahepatic cholangiocarcinoma (iCCA) originates in the intrahepatic biliary tree above the second order bile ducts. There are two primary histological subtypes of iCCA: small bile duct iCCAs which arise at the level of the smaller intrahepatic bile ducts, and large bile duct iCCAs which arise in the large intrahepatic bile ducts. Hepatic stem or progenitor cells and cuboidal cholangiocytes are the cells of origin of small bile duct iCCA, whereas large bile duct iCCAs arise from columnar mucous cholangiocytes or peribiliary glands. The molecular pathogenesis of iCCA is distinct from the other anatomic subtypes of CCA. Potentially actionable genomic aberrations that occur in iCCA include fibroblast growth factor receptor 2 (FGFR2) gene fusions, isocitrate dehydrogenase (IDH) 1 and 2 mutations, BRAF mutations, and neutrotrophic tyrosine receptor kinase (NTRK) gene fusions. Epigenetic aberrations that occur in iCCA include inactivating mutations of chromatin remodeling genes such as BAP1 and ARIDIA. Additionally, IDH 1/2 mutations lead to the production of oncometabolites with consequent widespread epigenetic changes. IDH inhibitors and FGFR inhibitors have now received FDA approval for IDH mutated and FGFR altered CCA, respectively. Immune checkpoint inhibition has received tissue agnostic FDA approval for mismatch repair deficient/MSI high CCAs. Other targeted therapies such as PARP inhibitors and CDK4/6 inhibitors are under active investigation. Citation Format: Sumera I Ilyas. Molecular Pathogenesis and Cells of Origin of Intrahepatic Cholangiocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA21.
Abstract IA19: Impact of single checkpoint inhibitors and biomarkers of response
Authors: Anthony El-Khoueiry
Journal: Clinical Cancer Research (2022)

Abstract Single agent anti PD-1 antibodies have shown consistent safety and efficacy for the treatment of advanced hepatocellular carcinoma (HCC). Response rates range between 15 and 20% and the rate of grade 3 and 4 adverse events is generally below 25%. Recently, the HIMALAYA trial showed that durvalumab was non-inferior to sorafenib for first-line treatment of HCC. Further, Keynote-394 showed that pembrolizumab improved survival compared to placebo in second line treatment of HCC. Nivolumab was evaluated in a dedicated cohort of Checkmate 040 in patients with child pugh B cirrhosis and determined to have a manageable safety profile, similar to that in child pugh A. Given the fact that immunotherapy-based combinations are the current standard of care for advanced HCC, and given the absence of biomarkers for patient selection, the use of single agent anti PD-1 or PD-L1 antibodies in advanced first line HCC treatment is limited to patients who are not candidates for combination therapy or patients with compromised liver function. Single agent anti PD-1/PD-L1 antibodies are being evaluated in the adjuvant setting and in combination with liver directed therapy. Emerging biomarker data suggest an association between T cell inflammation signature and outcome with single agent anti PD-1 and PD-L1 agents. Further research is needed to validate the early biomarker data. Citation Format: Anthony El-Khoueiry. Impact of single checkpoint inhibitors and biomarkers of response [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA19.
Abstract IA18: Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH)
Authors: Mark Yarchoan
Journal: Clinical Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) usually arises in the setting of liver cirrhosis from viral or non-viral causes. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is a rising cause of HCC in the United States and many other parts of the world. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD1) or its ligand have improved outcomes for patients with advanced HCC. In general, clinical biomarkers are not currently used to identify patients most likely to benefit from systemic immunotherapy in HCC, and whether etiology has any effect on immunotherapy responses in HCC has been unclear. In this session, we will review recent preclinical data suggesting that NASH may impair immune responses in HCC. We will also review data from The Cancer Genome Atlas (TCGA) comparing the tumor immune microenvironment of viral-associated and non-viral HCC, and review the preponderance of clinical evidence indicating that HBV, HCV, and non-viral HCC all derive clinical benefit from immune checkpoint inhibitor therapy. Citation Format: Mark Yarchoan. Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH) [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA18.
Clinical outcomes in patients with chronic lymphocytic leukemia with disease progression on ibrutinib
Authors: Paul J. Hampel, Kari G. Rabe, Timothy G. Call, Wei Ding, Jose F. Leis, Asher A. Chanan-Khan, Saad S. Kenderian, Eli Muchtar, Yucai Wang, Sikander Ailawadhi, Amber B. Koehler, Ricardo Parrondo, Susan M. Schwager, Taimur Sher, Curtis A. Hanson, Min Shi, Daniel L. Van Dyke, Esteban Braggio, Susan L. Slager, Neil E. Kay, Sameer A. Parikh
Journal: Blood Cancer Journal (2022)

Patients with chronic lymphocytic leukemia (CLL) with disease progression on ibrutinib have worse outcomes compared to patients stopping ibrutinib due to toxicity. A better understanding of expected outcomes in these patients is necessary to establish a benchmark for evaluating novel agents currently available and in development. We evaluated outcomes of 144 patients with CLL treated at Mayo Clinic with 2018 iwCLL disease progression on ibrutinib. The median overall survival (OS) for the entire cohort was 25.5 months; it was 29.8 months and 8.3 months among patients with CLL progression (n = 104) and Richter transformation (n = 38), respectively. Longer OS was observed among patients with CLL progression who had received ibrutinib in the frontline compared to relapsed/refractory setting (not reached versus 28.5 months; p = 0.04), but was similar amongst patients treated with 1, 2, or ≥3 prior lines (18.5, 30.9, and 26.0 months, respectively, p = 0.24). Among patients with CLL disease progression on ibrutinib, OS was significantly longer when next-line treatment was chimeric antigen receptor T-cell therapy (median not reached) or venetoclax-based treatment (median 29.8 months) compared to other approved treatments, such as chemoimmunotherapy, phosphoinositide 3'-kinase inhibitors, and anti-CD20 monoclonal antibodies (9.1 months; p = 0.03). These findings suggest an unmet need for this growing patient population.
Abstract IA26: FGFR2 fusion inhibitors: Clinical benefit and mechanisms of resistance
Authors: Mitesh Borad
Journal: Clinical Cancer Research (2022)

Abstract The fibroblast growth factor pathway (FGFR) has been implicated in a subset of hepatobiliary cancers. Predominant amongst these are fusions/rearrangements for FGFR2 in ~10-15% of intrahepatic cholangiocarcinomas. In this talk we will review: (1) the FGFR pathway and its role in normal physiology, (2) sequencing studies in cholangiocarcinoma with emphasis on discovery of FGFR2 fusions, (3) clinical data for FDA approved FGFR small molecule tyrosine kinase inhibitors, (4) clinical data for second and third generation FGFR inhibitors, (5) determinants of response to therapy for FGFR inhibitors, (6) mechanisms of resistance to FGFR inhibitors and (7) on and off target toxicities for first generation FGFR inhibitors. Citation Format: Mitesh Borad. FGFR2 fusion inhibitors: Clinical benefit and mechanisms of resistance [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA26.
Abstract PO014: Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model
Authors: Jun Yang
Journal: Clinical Cancer Research (2022)

Abstract Lack of relevant animal models and cell lines of hepatoblastoma hampers our understanding pathogenesis of and identifying therapeutic targets for this neoplasm. We report a liver-specific MYC-driven hepatoblastoma murine model that faithfully recapitulates the pathological features of mixed fetal and embryonal hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of human disease. Single-cell RNA-sequencing (scRNA-seq) and spatiotranscriptomics identified distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we mapped the cancer dependency genes using CRISPR-Cas9 screening and identified druggable targets shared with human hepatoblastoma (i.e., CDK7, CDK9, PRMT1, PRMT5). Our screen also revealed oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is the mainstay for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identified modifiers whose loss-of-function synergizes and antagonizes with the effect of chemotherapy. The combination of PRKDC inhibition and chemotherapy greatly enhances therapeutic efficacy. Our studies have provided and characterized useful resources including disease models and identified potential therapeutic targets of high-risk hepatoblastoma. Citation Format: Jun Yang. Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO014.
Abstract IA01: Molecular drivers in hepatocellular carcinoma: The story of what we know and what are we missing
Authors: Jessica Zucman-Rossi
Journal: Clinical Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, both at the molecular and histological level. High-throughput sequencing and gene expression profiling have identified distinct transcriptomic subclasses and recurrently altered cancer driver genes. Several HCC subtypes characterized by histological features have also been identified. HCC phenotype appears to be closely related to particular gene mutation and driven by various oncogenic pathway alterations. Identification of the origin of HCC development and their trajectory of progression is important to understand tumor evolution and to identify the mechanisms of tumor response or resistance to therapies. We will review the early and late molecular alterations driving HCC occurrence and progression of tumors in the context of patient lifespan and exposure to environmental factors. Several questions remain to be answered, in particular on the identification of the cells at the origin of the malignant transformation into HCC and the mechanism of escape to the immunological monitoring. Citation Format: Jessica Zucman-Rossi. Molecular drivers in hepatocellular carcinoma: The story of what we know and what are we missing [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA01.
Abstract IA27: Trial Design in the era of precision oncology and combination therapies
Authors: John Bridgewater
Journal: Clinical Cancer Research (2022)

Abstract Clinical studies in precision medicine have tested the long-standing conventional model built around the randomized phase 3 study. Multiple uncertainties with respect to incidence, molecular profiling and realistic level of evidence have challenged tried and tested paradigms for trialists, clinicians and reimbursement authorities. I will discuss how we determine the incidence of uncommon subgroups of uncommon cancers, the definition of these subgroups using bespoke clinical and molecular criteria, the availability, efficacy and heterogeneity of molecular testing, the availability of specialists, the quality of the data in order to permit reimbursement and the sustainability of treating patients in the era of precision medicine. With the continuing evolution of precision medicine, old dogs will have to become familiar with many new tricks. Citation Format: John Bridgewater. Trial Design in the era of precision oncology and combination therapies [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA27.
Abstract IA17: Assessing response and time-to-event end-points: RECIST and mRECIST
Authors: Riccardo Lencioni
Journal: Clinical Cancer Research (2022)

Abstract In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). mRECIST was intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease. mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches including immunotherapy combination therapies, there is a need to further refine and clarify some concepts around the performance of mRECIST. Citation Format: Riccardo Lencioni. Assessing response and time-to-event end-points: RECIST and mRECIST [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA17.